Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Moreover, in those patients who do experience symptomatic relief following conventional anti-depressant treatment, clinical improvement is not evident for 3-4 weeks.
Some effective antidepressant medications such as tricylic antidepressant drugs have potent antimuscarinic effects [7-9]; however, there has been no study to evaluate systematically the efficacy of an anticholinergic as an antidepressant agent. Successful clinical treatment of depression has depended on the use of tricyclic agents, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRI). Moreover, over the past two decades of antidepressant drug development, the muscarinic antagonist effects of early antidepressant drugs (i.e., the tricyclic antidepressant agents) were viewed almost exclusively as producing unwanted side effects without contributing at all to therapeutic effects [14-16]. As a result, efforts to develop new antidepressant treatments included an emphasis on developing compounds that specifically did not have antagonist effects at muscarinic cholinergic receptors [17].